Reinforced biologic material

ABSTRACT

The present disclosure provides an implantable medical device comprising a composite graft material including a first biologic component, such as an acellular tissue matrix, and a second non-biologic component.

This application is a continuation of application Ser. No. 15/210,309,filed Jul. 14, 2016 (allowed), which is a continuation of applicationSer. No. 13/616,556, filed Sep. 14, 2012 and issued as U.S. Pat. No.9,421,306, which is a continuation of application Ser. No. 12/621,890,filed Nov. 19, 2009 and issued as U.S. Pat. No. 8,333,803, and claimspriority under 35 U.S.C. § 119 to U.S. Provisional Patent ApplicationNo. 61/117,068, which was filed on Nov. 21, 2008, each of which arehereby incorporated by reference.

This invention was made with government support under U.S. Army ContractNumber W81XWH-06-0136. Accordingly, the government has certain rights inthe invention.

The present disclosure generally relates to implantable medical devicesand methods for making the same.

Surgeons performing ligament and tendon replacement in mammals have longsought a material that approximates the load transmission andperformance of the native ligament and tendon structures. Syntheticligaments and tendons have been made from steel, polyester,polyurethane, polyethylene, Nylons, polytetrafluoroethylene, carbonfiber and other man-made materials. Combinations of anyone or more ofthe aforementioned materials have also been used to manufacturesynthetic ligaments. However, synthetics typically experience decreasingfunctional capability over time and can wear out, fray, and/orparticulate in relatively short time periods after implantation.

As an alternative to synthetic materials, natural ligament or tendontissue harvested from autografts and/or allograft sources may also beused in ligament or tendon replacement procedures. As with syntheticmaterials, for both autografts and allografts, long-term recovery offunctional parameters (e.g., failure load, linear and tangentialstiffness, failure stress, and strain at failure) remains significantlyreduced compared to native ligament, tendon or other soft tissuestructures.

There is a need for a material for ligament, tendon, and other softtissue repair and replacement that is free of donor site morbidityassociated with autografts, has improved failure rates over traditionalallografts and synthetic tissues, and better approximates native tissuebiomechanical performance.

This discussion of the background disclosure is included to place thepresent disclosure in context. It is not an admission that any of thebackground material previously described was published, known, or partof the common general knowledge as at the priority date of the presentdisclosure and claims.

As used herein, the term, “comprise” and variations thereof, such as“comprising” and “comprises,” is not intended to exclude otheradditives, components, integers or steps.

SUMMARY

In some embodiments, an implantable medical device is provided. Thedevice comprises a plurality of first elongate non-biologic elements, atleast a portion of which are under a tensile or compressive stress priorto implantation; at least one biologic component surrounding at least aportion of the plurality of first elongate elements; and at least onesecond elongate non-biologic element, wherein the at least one secondelement secures at least one end portion of the plurality of firstelongate non-biologic elements.

In some embodiments, a method of making a composite prosthesis isprovided. The method comprises providing a plurality of first elongatenon-biologic elements; applying a load to the plurality of firstelongate non-biologic elements; covering at least a portion of theplurality of first elongate non-biologic elements with at least onebiologic component; and securing the plurality of first elongatenon-biologic elements with at least one second elongate non-biologicelement.

In some embodiments, an implantable medical device is provided. Thedevice comprises at least one non-biologic core material under tensilestress; and at least one biologic element disposed about the at leastone non-biologic core, the at least one biologic element comprising abiomatrix; wherein the at least one non-biologic core bears a greatertensile load at a time of implantation than the at least one biologicelement, while transmitting stress to the at least one biologic element;and after implantation, the at least one non-biologic core graduallyweakens, thereby dynamically transferring additional tensile load to theat least one biologic element.

In some embodiments, a method of making a composite prosthesis isprovided. The method comprises providing at least one non-biologic core;applying a tensile load to the non-biologic core; and disposing at leastone biologic element about the at least one non-biologic core, the atleast one biologic element comprising a biomatrix; wherein the at leastone non-biologic core bears a greater tensile load at a time ofimplantation than the at least one biologic element, while transmittingstress to the at least one biologic element; and after implantation, theat least one non-biologic core gradually weakens, thereby dynamicallytransferring additional tensile load to the at least one biologicelement.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exemplary stress-strain curve for various graft materials.

FIG. 2 is a graph illustrating the concept of functional target loadingof a composite graft material.

FIGS. 3 and 3A show an exemplary embodiment of a composite graftmaterial.

FIG. 4A shows an exemplary embodiment of a composite graft materialemploying a non-biologic component in the form of a flat sheet.

FIG. 4B shows an exemplary embodiment of a rolled composite graftmaterial.

FIG. 5 shows an exemplary embodiment of an interference screw foranchoring a composite graft material.

FIG. 6 is a graph depicting the load capacity over time of certaincomponents of a composite graft material, according to certainembodiments.

FIG. 7 is a graph illustrating the effect of pre-tensioning on thestress-strain curve of various graft materials, according to certainembodiments.

FIG. 8A illustrates a plurality of elongate non-biologic components,according to certain embodiments.

FIG. 8B illustrates a sheath of bioabsorbable material, according tocertain embodiments.

FIG. 9 illustrates a plurality of elongate non-biologic components,according to certain embodiments.

FIGS. 10A-10G illustrate exemplary embodiments of composite grafts,according to certain embodiments.

DETAILED DESCRIPTION

The present disclosure relates to implantable medical devices andmethods of producing and using such devices. In certain embodiments, themedical devices include composite materials/tissues. In someembodiments, the composite materials comprise both biologic andnon-biologic components suitable for use as a tissue implant orreplacement for a ligament, tendon, or soft tissue structures. In someembodiments, the composite is constructed with at least two materials,for example, a non-biologic component (e.g., a synthetic polymer) and abiologic component (e.g., a biomatrix). In some embodiments, thenon-biologic component is combined with the biologic component to createa composite tissue that utilizes certain properties of the constituentmaterials.

The non-biologic component, such as a synthetic polymer, is designed toprovide appropriate mechanical properties to the composite structureimmediately after implantation and to transmit higher loads overtraditional biologic implants when the material is implanted. In someembodiments, the non-biologic component transmits some load and motionto the biologic component. In some embodiments, the biologic componentis designed to assist in longer-term healing. In some embodiments, themotion/load distribution between the non-biologic component and thebiologic component of the composite material contributes to anenvironment suited for tissue healing. In some embodiments, the biologiccomponent, via a biomatrix, facilitates a process of becoming ortransforming from a basic biologic tissue scaffold to a tissue similarto the native tissue being replaced (e.g., a ligament-like tissue) byencouraging or allowing the in-growth of native cells within the matrixstructure of the biologic component.

Composite Material:

Tissue grafts generally experience some change or deterioration inmechanical characteristics within the first month after implantation.Such mechanical performance characteristics may include, for example,load performance, elasticity and stiffness. Recovery of some or all ofthe mechanical performance characteristics typically progresses over oneto two years after implantation.

Generally, synthetic materials used in tissue replacement impart aninitial load capacity at the time of implantation that can be equal toor higher than natural tissue implants. But, synthetic tissue implantstypically experience a continual, and at times, significant loss in loadcapacity over the first two years after implantation.

Natural fiber tissue implants, such as autografts and allografts,experience a significant drop in load capacity soon after implantation,with an ultimate recovery of load capacity and other mechanicalperformance characteristics of between 50-60% of the starting capacityof the natural graft tissue.

In some embodiments, the composite graft material of the presentdisclosure combines the benefits of typical synthetic polymer tissuegrafts (i.e., relatively high initial mechanical performancecharacteristics) with the prohealing and better long-term mechanicalcharacteristics of natural tissue grafts. The composite tissue may, forexample, perform as a summation of its individual components, or betterthan a summation of the individual components. For example, a typicalsynthetic implant experiences degradation with decreasing physicalperformance over time. The composite tissue of the present disclosureprovides a layer of biomatrix around or over the synthetic component,which can result in slower degradation than would be exhibited by atypical, uncoated synthetic implant.

In some embodiments, the first biologic component and the secondnon-biologic component of the composite graft material are constructedto produce mechanical performance parameters desired for the specifictissue being replaced. For example, in constructing a composite materialfor ligament replacement, it may be desirable to have an ultimate loadfailure of approximately 1800 N. If the constructed first componentbiomatrix material provides an ultimate failure load of only 400 N, thenthe synthetic second component can be configured to provide theremaining 1400 N to produce a composite graft material having thedesired performance characteristics. Similarly, if the desired stiffnessfor the ACL replacement graft is 200 N/mm and the biomatrix of the firstcomponent provides only 50 N/mm, then the polymeric material of thesecond component can be configured to provide the remaining stiffness of150 N/mm.

FIG. 1 illustrates an exemplary stress-strain curve of variousmaterials. Line 2 illustrates a desired curve for an ideal graft. Line 4illustrates an exemplary actual stress-strain curve for either asynthetic or natural tissue graft. As can be seen, the actual grafts arenot capable of reaching the desired stress levels for the same amount ofstrain sought in a desired graft.

In some embodiments, the composite graft material described hereinincludes both a biologic and a non-biologic material (e.g., preparationof a weave, or of a braid or of a crimp, or of some other configurationsuch as a layered or rolled configuration), which raises thestress-strain curve for the composite graft material along the y axis.Consequently, line 6 illustrates a modified, composite graft materialshaving improved performance compared to synthetic or biologic grafts.

FIG. 2 illustrates the load capacity versus time since implantation ofthe composite graft material to demonstrate the concept of functionaltarget loading of the composite graft material. The biologic materialalone has a relatively low load capacity at the time of implantation,but as the body subsequently heals, the load capacity of the biologiccomponent increases over time. Conversely, a polymer graft'sload-bearing capacity is relatively high at implantation, but decreasessubsequently. It has been found that a composite graft materialconsistent with the present disclosure (labeled “Hybrid”), whichcomprises both a biologic component having a biomatrix and anon-biologic component (such as a polymer), has a relatively stableload-bearing capacity over time (that is, the load bearing capacitystarts out, and remains, in the “Target Range”).

The non-biologic component can be coupled with the biologic component ina variety of ways. For example, the biologic component may be disposedaround the non-biologic component (as exemplified in FIG. 3), or viceversa. Alternatively, the biologic component may be embedded within acoating, a knit, weave, braid or other structure of the non-biologiccomponent. To provide load sharing between the non-biologic componentand the biologic component, the two components may, for example, becomingled or layered and rolled tightly around one another. In someembodiments, such structures create friction between the components. Insome embodiments, compressive force is added to the layered construct,e.g., by including securing straps similar to a belt and hoop design.

FIG. 3 depicts an exemplary embodiment of the composite graft materialof the present disclosure. As shown, tubular non-biologic component 40is provided having upper portion 42, upper taper region 43, lowerportion 44, lower taper region 45, and neck portion 46. Biologiccomponent 50 is also provided and is illustrated as a sheet with anupper edge 51 and a lower edge 52. In some embodiments, biologiccomponent 50 is wrapped around neck portion 46 of non-biologic component40 so that upper edge 51 is in contact proximal to or with upper taperregion 43 and lower edge 52 is in contact proximal to or with lowertaper region 45. Biologic component 50 can wrap or encircle neck portion46 one or more times to form a multi-layer wrap. For example, biologiccomponent 50 can wrap around neck portion 46 of non-biologic component40 one time, two times, three times, four times, five times, or more.Biologic component 50 can similarly wrap around upper portion 42 andlower portion 43 of non-biologic component 40 one or more times.

In some embodiments, after wrapping biologic component 50 aroundnon-biologic component 40, upper portion 42 of non-biologic component 40may be rolled or folded over wrapped biologic component 50 and towardlower portion 44 such that at least some of upper portion 42 extendsbelow the upper taper region 43 and overlaps neck portion 46. In someembodiments, lower portion 44 is rolled or folded over biologiccomponent 50 and toward upper portion 42 such that at least some oflower portion 44 extends above lower taper region 45 and overlaps neckportion 46, as depicted in FIG. 3A.

In some embodiments, securing straps and/or tethers 60 are provided toapply compressive force to the rolled composite graft material andprovide frictional contact between the biologic component and thenon-biologic component. The securing straps may, for example, beconstructed of the same material as non-biologic component 40. Tethers60 may also be made from the same material as the non-biologic componentof the composite material or from other materials such as stainlesssteel or non-bioabsorbable polymers.

Tethers 60 may be useful during implantation or construction of thecomposite graft material. For example, tethers 60 may be used to pullthe composite graft material into a bone tunnel. Tethers 60 may also beused, for example, to anchor non-biologic component 40 while biologiccomponent 50 is wrapped around non-biologic component 40.

Tethers 60 can be attached to non-biologic component 40 in various ways.For example, tethers 60 may be woven, knitted, or braided intonon-biologic component 40. Tethers 60 may also be integrated into thenon-biologic component 40, and may be configured to detach fromnon-biologic component 40. In some embodiments, tethers 60 are used as aradiopaque marker.

In some embodiments, a composite graft material in accordance with thepresent disclosure is constructed with a non-biologic component in theform of a flat sheet, as illustrated in FIG. 4A. Non-biologic component80 includes upper portion 82, lower portion 84, neck portion 85, andneck lateral edge 86. Upper portion 82 and lower portion 84 may be madeof same or different non-biologic material as neck portion 85. Forexample, neck portion 85 may comprise a high tensile strength textile ofa bioabsorbable polymer, while upper portion 82 and lower portion 84comprise a relatively low tensile strength textile of a bioabsorbablepolymer. Non-biologic component 80 may also, for example, comprisenon-textile polymers as previously described.

Referring still to FIG. 4A, biologic component 50 may, for example, beprovided as a flat sheet of biologic material comprising an acellulartissue matrix having an upper edge 51, a lower edge 52, and a lateraledge 53. In some embodiments, non-biologic component 80 is placed on topof biologic component 50 such that neck lateral edge 86 of non-biologiccomponent 80 aligns with lateral edge 53 of biologic component 50, andthe two layered components are then rolled such that neck lateral edge86 and lateral edge 53 remain aligned and form the innermost portion ofthe roll.

FIG. 4B shows a non-limiting embodiment of a rolled composite graftmaterial in accordance with the present disclosure. This rolledcomposite graft material is constructed as described above, with thebiologic component 50 forming the outside surface of the rolledstructure and neck lateral edge 86 forming the inner most portion of therolled structure. Upper portion 82 and lower portion 84 form amulti-layered non-biologic material within the rolled structure and canprovide added strength and material to secure the composite graftmaterial to surrounding native tissue, for example, by interferencescrews.

In some embodiments, the composite graft material is designed to matchthe size (length, width, thickness) of the natural structure (i.e.,ligament or tendon) it will replace. For example, for an ACL, thecomposite graft material may be designed to be about 6 to 12 mm indiameter for a unibody device or 3 to 6 mm in diameter if separated intotwo bundles. It is known that within the body, specific ligament sizesslide and fit between bony structures. A ligament that is too small maynot distribute stress evenly, and a ligament that is too large mayinterfere with or rub against one or both bony structures. Thus,matching the size of the implant material with the native tissue to beremoved can reduce complications.

In some embodiments, the size of the composite graft material iscustomized to the patient and the tissue being replaced. For example,one or more rolls of biologic and non-biologic components can be addedor removed by varying the size or length of the individual components.The longer the pre-rolled composite construct, the more rolls arepossible, thereby producing a finished composite graft material having agreater diameter. Alternatively the number of layers of individualcomponents can be altered to adjust the final size of the graftmaterial. For example, a composite construct comprising a tissue layer,a polymer layer, and another tissue layer would provide a largerdiameter graft than a composite construct of only two layers.

Various techniques may be employed to anchor or fix the composite graftmaterial to an implantation site. For example, in an ACL replacement,interference screws are used for anchoring cadaver or autograftmaterials. In some embodiments, an interference screw is provided thatanchors the composite graft material. This is shown in FIG. 5, whereininterference screw 90 is inserted into the core of graft 94 such that asinterference screw 90 advances, screw 90 expands the diameter of graft94 to exert outwardly radial pressure against the surround bone tunnel.Other common fixation devices may be used, including cross-pins,endobuttons, sutures, or staples.

In some embodiments, screws or other anchoring devices can be made oftitanium, stainless steel, biodegradable metals, biodegradable orbioabsorbable polymers such as polylactic acid (PIA), polyglycolic acid(PGA), polylactideglycolide acid (PLGA), polydioxanone (PDO), orpolycaprolactone (PCL). As a non-limiting example of a typicalinterference screw, non-limiting mention is made of the RCI screwmanufactured by Smith and Nephew, Andover Mass., 01810.

The biologic component comprising the biomatrix material of thedisclosed composite graft material may benefit from the stress ofordinary movement following implantation. For example, the stresses andstrains caused by ordinary activity may cause the biologic tissue to bestronger and recover to a greater ultimate strength due to normalremodeling facilitated by mechanical forces.

In some embodiments, the non-biologic component of the composite tissuegraft material described herein is preloaded with a tensile load rangingfrom greater than 0 N to about 1800 N (e.g., from about 0.1 to about1700 N; about 10 to about 1600 N, about 100 to about 1500 N, about 150to 1400 N, about 200 to 1300 N, etc.). The initial stress on strain onthe non-biologic material is partially transferred to the biologiccomponent, with the non-biologic component assuming more of the appliedstress after reaching a preloaded limit.

As previously discussed, FIG. 1 illustrates an exemplary stress-straincurve of various tissue grafts. Line 2 illustrates a desired curve foran ideal graft. Line 4 illustrates an exemplary actual stress-straincurve for either a synthetic or natural tissue graft. As can be seen,natural grafts are not capable of reaching the desired stress levels forthe same amount of strain sought in a desired graft. In contrast,because it incorporates both biologic and non-biologic materials, someembodiments of the composite graft materials described herein mayexhibit a stress-strain curve that is shifted along the y axis.Consequently, line 6 of FIG. 1 illustrates a composite graft materialhaving improved load capacity performance over actual synthetic orbiologic grafts.

In some embodiments, the non-biologic component, the biologic component,or both the non-biologic and biologic components can be placed undertensile stress prior to implantation. This has the effect of moving thestress-strain curve of the material along the x-axis as depicted in FIG.7. Line 2 illustrates a desired curve for an ideal graft material. Line5 illustrates an actual curve for synthetic or natural tissue graft, andline 7 illustrates a curve of a composite graft material that has beensubjected to preloading with a tensile stress.

In some embodiments, a portion of the tensile load applied to thenon-biologic component is transferred to the biologic component. Theinitial strain applied is selected to be high enough to prevent orretard resorption of the biologic component upon implantation, but lowenough to avoid physically damaging the biologic tissue. For example,the strain applied to the biologic component may range from less than orequal to 40%, less than or equal to 35%, less than or equal to 30%, lessthan or equal to 25%, less than or equal to 20%, less than or equal to15%, less than or equal to 10%, less than or equal to 5%, and less thanor equal to 1% of the initial strain applied to the non-biologicmaterial by an initial tensile load. The initial strain applied to thebiologic component may also fall within any range specified by acombination of the above recited endpoints, e.g., from greater than orequal to 1% to less than or equal to 40%, from greater than or equal to5% to less than or equal to 35%, from greater than or equal to 10% toless than or equal to 30%, and from greater than or equal to 15% to lessthan or equal to 25% of the initial strain imparted to the non-biologiccomponent by an initial tensile load.

In some embodiments, a composite graft material can be made using aplurality of elongate non-biologic components wrapped with at least onelayer of a biologic component. The elongate non-biologic components canbe placed under a tensile stress ranging from greater than 0 N to 1800 N(e.g., from about 100 to about 1700 N; about 200 to about 1600 N, about300 to about 1500 N, etc.), prior to wrapping with the biologiccomponent. The plurality of elongate non-biologic components may also bepre-wrapped in a sheath comprising non-biologic components. At least oneend of the non-biologic components can be secured (e.g., by whipping,wrapping, and/or winding) with an additional elongate component to formmultiple layers with a raised surface at the end. The biologic componentmay, for example, be wrapped around the secured plurality of elongatenon-biologic components and secured with a smaller fastening or whippingadjacent to the raised surface formed by the secured biologic component.

In some embodiments, all of the plurality of elongate non-biologiccomponents can be placed under a tensile stress prior to forming thecomposite graft material. In other embodiments, a percentage of theelongate non-biologic components can be placed under tensile stressprior to forming the composite graft material, while a percentage of theelongate biologic components can be free of tensile stress prior toforming the composite graft material. Further, in some embodiments, theplurality of elongate non-biologic components and the biologic componentcan be placed under a tensile stress prior to final assembly of thegraft.

FIG. 8A illustrates a plurality of elongate non-biologic components 810.The plurality of elongate components can be bundled as a group havingbetween 200 and 1200 individual elongate components, depending on thesize and mechanical requirements of the composite graft material. Insome embodiments, the number of individual components can be between 400and 1000, 600 and 800, or approximately 700 individual components. Theelongate non-biologic components may also be bioabsorbable. Theplurality of elongate components 810 can have a proximal end 812 and adistal end 814. Securing elements 816 (e.g., whipping elements) can bewrapped around the plurality of components to secure the components 810as a bundle 818. The plurality of elongate components 810 can be placedunder a tensile load prior to securing. Securing elements 816 areattached to the plurality of components 810 in such a manner as toretain the preloaded tensile stress in the plurality of elongatecomponents.

FIG. 8B illustrates a non-limiting embodiment of the present disclosure,wherein sheath 815 of bioabsorbable non-biologic material is wrappedaround the plurality of elongate components 810. The plurality ofelongate components may be loaded with a tensile stress independently ofthe sheath, or the sheath and plurality of elongate components can beloaded together. Securing elements 816 can be wrapped around and overthe sheath 815 of non-biologic material.

In some embodiments, a biologic component containing a biomatrix is usedto cover or coat at least a portion of the plurality of elongatenon-biologic components. In some embodiments, the biologic component maybe in the form of a sheet wrapped around a secured plurality of elongatenon-biologic components. As a non-limiting example, FIG. 9 illustrates aplurality of elongate non-biologic components 910 having a proximal end912 and distal end 914. Securing elements 916 are wrapped around theplurality of elongate components to secure the elongate components as abundle 918 and maintain a preloaded tensile stress in the elongatebundle 918. Securing elements 916 can be wrapped in multiple layers toform a raised surface 917.

In some embodiments, biologic component 920 may be wrapped in one ormore layers around the elongate bundle 918 and secured by secondsecuring elements 922 proximate the raised surface 917 formed bysecuring elements 916. Second securing elements 922 can be secured aboutthe biologic component 920 and the elongate bundle 918 such that thebiologic component is free from tensile stress. In some embodiments, thebiologic component 920 can be placed under tensile stress and secured bysecond securing elements 922 to maintain the tensile load in thebiologic component 920. In some embodiments, the tensile load in thebiologic component can range from greater than 0 N to about 1800 N, fromgreater than 0 to about 600 N, from about 50 to about 300 N, or fromabout 100 to about 200 N. In some embodiments, the biologic component920 may, be pre-loaded to the same tensile stress as the plurality ofelongate components 910. In some embodiments, the biologic component 920may also be pre-loaded to tensile stress less than that of the pluralityof elongate components 910. In some embodiments, the biologic component920 can be pre-loaded to a tensile stress more than that of theplurality of elongate components 910.

In some embodiments, the biologic component can be paired with theplurality of elongate elements in a variety of ways, including: as asingle layer sheet wrapped about the elongate non-biologic components;in a jellyroll manner wherein the biologic component is wrapped inmultiple layers; as a non-uniform sheet such that multiple layers ofbiologic component are not concentric about the plurality of elongateelements; as a top sheath wrapped or coated over an inner sheath ofnon-biologic material; as a coating about the outer surface of thebundle of elongate non-biologic elements; and/or as a coatinginterspersed throughout the bundle of elongate non-biologic components.

FIG. 10A shows composite graft material 1000 comprising a plurality ofelongate non-biologic elements 1010 and biologic component 1020, whereinbiologic component 1020 is wrapped as a sheet in a single layer over theplurality of elongate elements 1010. FIG. 10B shows a composite graftmaterial 1001 comprising a plurality of elongate non-biologic elements1011 and biologic component 1021, wherein biologic component 1021 iswrapped as a sheet in a jellyroll fashion with multiple layers over theplurality of elongate elements 1011. FIG. 10C shows a composite graftmaterial 1002 comprising a plurality of elongate non-biologic elements1012 and biologic component 1022, wherein biologic component 1022 iswrapped as a non-uniform sheet in a jellyroll fashion with multiplenon-concentric layers over the plurality of elongate elements 1012. FIG.10D shows a composite graft material 1003 comprising a plurality ofelongate non-biologic elements 1013 and biologic component 1023, whereinbiologic component 1023 is wrapped as a single layer sheet forming anouter sheath over inner sheath 1035 of non-biologic material. Innersheath 1035 is wrapped about the plurality of elongate non-biologiccomponents.

Biologic component 1020 may also be applied as a coating. The coatingcan, for example, be in the form of a liquid, a powder, or a spray, andmay be applied using any suitable technique.

FIG. 10E shows a composite graft material 1004 comprising a plurality ofelongate non-biologic elements 1014 and biologic component 1024, whereinbiologic component 1024 coats the outer surface of the plurality ofelongate elements 1015. FIG. 10F shows a composite graft material 1005comprising a plurality of elongate non-biologic elements and biologiccomponent 1025, wherein biologic component 1025 is interspersed betweenand coats the outer surfaces of the individual elongate elements in theplurality of elongate elements 1015, as shown in FIG. 10G.

In some embodiments, the plurality of elongate non-biologic elements aresecured by a securing material (e.g., a whipping material) such that thesecuring material is wound about the plurality of elongate non-biologicelements in a manner that is engageable with an anchor screw. Thesecuring material may, for example, be wound to create a screw-threadpattern having a pitch compatible with an anchoring screw to betterengage and lock the composite graft material to the anchoring screw uponimplantation in the patient. The material used to secure the tissue orbiologic component to the plurality of elongate non-biologic elementscan also be wound so as to have a screw-screw thread pattern engageablewith an anchoring screw. The securing material can form the male orfemale thread to the threads of the anchoring screw.

In some embodiments, the composite graft material may be used for ACLreplacement. In some embodiments, the composite graft material isdesigned to have the properties of a typical ACL, e.g., failure load(1200-2400 N); stiffness (150-300 N/mm); failure stress (18-28 MPa);strain at failure (20-35%); and modulus of elasticity (75-180 MPa).

In some embodiments, the natural mechanical and biologic properties ofnative ACL tissue may be matched, for example, by selecting andconstructing each component of a device to meet specific designrequirements. For example, a device meeting the general characteristicsof an ACL may be made with a non-biologic component having a modulus ofelasticity of about 140 MPa, a maximum rupture load or ultimate loadfailure of about 1200 N, and degradation resistance through 9 to 16months before construction of the composite graft material. In someembodiments, the biologic component exhibits a modulus of elasticity ofabout 55 MPa at the time of implantation and a maximum load at ruptureof approximately 600 N before construction of the composite graftmaterial.

In some embodiments, a composite graft material suitable for ACL repairmay, for example, exhibit a maximum rupture load of approximately 1400 Nbefore implantation. In some embodiments, the ultimate failure load ofthe non-biologic component of such an implant may decrease afterimplantation, while the failure load of the biologic component willincrease over time as native cells proliferate through the biomatrix. Insome embodiments, the implant may have an ultimate failure load ofapproximately 600 N within four months of implantation, approximately400 N within eight months of implantation, and approximately 1000 Nwithin 12 months of implantation. In some embodiments, the compositegraft material for ACL replacement may have a stiffness of approximately85 N/mm before implantation, approximately 106 N/mm within four monthsof implantation, approximately 78 N/mm within eight months of fixation,and approximately 176 N/mm within twelve months of fixation.

FIG. 6 depicts the load capacity over time of the first component, thesecond component and the composite graft material of a non-limitingexample of a composite ACL graft according to various embodiments. Asshown, the first component, line 8, exhibited a drop in load capacityimmediately following implantation with an increase in load capacitythereafter as native cells proliferated throughout the biomatrix. Line10 illustrates the initially high load capacity of the second componentafter implantation with a steady decrease in load capacity as the secondcomponent degraded over time. Line 12 shows the load capacity of thecomposite graft containing both the first component and the secondcomponent.

Biologic Component:

Biologic components that may be suitably used to produce composite graftmaterials can include any biologic material (e.g., whole tissue ortissue-derived material) with the properties described herein.Non-limiting examples of such biologic materials include biomatrices,such as acellular tissue matrices.

As used herein, the term “acellular tissue matrix” (“ATM”) refers to atissue-derived biomatrix structure that is made from any of a wide rangeof collagen-containing tissues by removing all or substantially allviable cells and all detectable subcellular components and/or debrisgenerated by killing cells. As used herein, an ATM lacking“substantially all viable cells” is an ATM in which the concentration ofviable cells is less than 1% of that in the tissue or organ from whichthe ATM was made.

Accordingly, in some non-limiting embodiments, the ATMs of the presentdisclosure contain epithelial basement membrane. In other non-limitingembodiments, the composite grafts disclosed herein lack or substantiallylack epithelial basement membrane. In some embodiments, the ATMs includea vascular basement membrane that may facilitate ingrowth of vascularendothelial cells.

ATM's suitable for use in the present disclosure may, for example,retain certain biologic functions, such as cell recognition, cellbinding, the ability to support cell spreading, cell proliferation,cellular in-growth and cell differentiation. Such functions may beprovided, for example, by undenatured collagenous proteins (e.g., type Icollagen) and a variety of non-collagenous molecules (e.g., proteinsthat serve as ligands for either molecules such as integrin receptors,molecules with high charge density such as glycosaminoglycans (e.g.,hyaluronan) or proteoglycans, or other adhesins). In some embodiments,the ATM's may retain certain structural functions, including maintenanceof histological architecture and maintenance of the three-dimensionalarray of the tissue's components. The ATM's described herein may also,for example, exhibit desirable physical characteristics such asstrength, elasticity, and durability, defined porosity, and retention ofmacromolecules.

ATMs suitable for use in the present disclosure may be crosslinked oruncrosslinked. In some non-limiting embodiments, the composite graftincludes an uncrosslinked ATM. The efficiency of the biologic functionsof an ATM can be measured, for example, by the ability of the ATM tosupport cell proliferation. In some embodiments of the presentdisclosure, the ATM exhibits at least 50% (e.g., at least: 50%; 60%;70%; 80%; 90%; 95%; 98%; 99%; 99.5%; 100%; or more than 100%, or anyranges between 50%-100%) of that of the native tissue or organ fromwhich the ATM is made.

In some embodiments, the biologic component, when implanted, is amenableto being remodeled by infiltrating cells such as differentiated cells ofthe relevant host tissue, stem cells such as mesenchymal stem cells, orprogenitor cells. Remodeling may be directed by the above-described ATMcomponents and signals from the surrounding host tissue (such ascytokines, extracellular matrix components, biomechanical stimuli, andbioelectrical stimuli). For example, the presence of mesenchymal stemcells in the bone marrow and the peripheral circulation has beendocumented in the literature and shown to regenerate a variety ofmusculoskeletal tissues [Caplan (1991) J. Orthop. Res. 9:641-650; Caplan(1994) Clin. Plast. Surg. 21:429-435; and Caplan et al. (1997) Clin.Orthop. 342:254-269]. Additionally, in some embodiments, the graft willprovide some degree (greater than threshold) of tensile andbiomechanical strength during the remodeling process.

An ATM in accordance with the present disclosure may be manufacturedfrom a variety of source tissues. For example, the ATM may be producedfrom any collagen-containing soft tissue and musculo-skeletonal tissue(e.g., dermis, fascia, pericardium, dura, umbilical cords, placentae,cardiac valves, ligaments, tendons, vascular tissue (arteries and veinssuch as saphenous veins), neural connective tissue, urinary bladdertissue, ureter tissue, or intestinal tissue), as long as theabove-described properties are retained by the matrix. Moreover, thetissues in which the matrices containing the ATM are placed may includeany tissue that can be remodeled by invading or infiltrating cells.Non-limiting examples of such tissues include skeletal tissues such asbone, cartilage, ligaments, fascia, and tendon. Other tissues in whichany of the above grafts can be placed include, for example, skin,gingiva, dura, myocardium, vascular tissue, neural tissue, striatedmuscle, smooth muscle, bladder wall, ureter tissue, intestine, andurethra tissue.

While an acellular tissue matrix may be made from one or moreindividuals of the same species as the recipient of the acellular tissuematrix graft, this is not necessarily the case. Thus, for example, anacellular tissue matrix may be made from porcine tissue and implanted ina human patient. Species that can serve as recipients of acellulartissue matrix and donors of tissues or organs for the production of theacellular tissue matrix include, without limitation, mammals, such ashumans, nonhuman primates (e.g., monkeys, baboons, or chimpanzees),pigs, cows, horses, goats, sheep, dogs, cats, rabbits, guinea pigs,gerbils, hamsters, rats, or mice.

As an example of suitable porcine-derived tissue, non-limiting mentionis Strattice™, which is a porcine dermal tissue produced by LifecellCorp, Branchburg, N.J. The tissue matrix may be derived from porcineskin by removing the epidermis while leaving the dermal matrixsubstantially intact. In some embodiments, the porcine-derived tissuematrix may facilitate tissue ingrowth and remodeling with the patient'sown cells. In other embodiments, the material can include a collagenousmatrix derived from human cadaver skin (e.g. AlloDerm™, Lifecell Corp,Branchburg, N.J.) that has been processed to remove both the epidermisand cells.

In general, the steps involved in the production of an acellular tissuematrix include harvesting the tissue from a donor (e.g., a human cadaveror animal source) and cell removal under conditions that preservebiologic and structural function. In certain embodiments, the processincludes chemical treatment to stabilize the tissue and avoidbiochemical and structural degradation together with or before cellremoval. In various embodiments, the stabilizing solution arrests andprevents osmotic, hypoxic, autolytic, and proteolytic degradation,protects against microbial contamination, and reduces mechanical damagethat can occur with tissues that contain, for example, smooth musclecomponents (e.g., blood vessels). The stabilizing solution may containan appropriate buffer, one or more antioxidants, one or more oncoticagents, one or more antibiotics, one or more protease inhibitors, and/orone or more a smooth muscle relaxant.

The tissue is then placed in a decellularization solution to removeviable cells (e.g., epithelial cells, endothelial cells, smooth musclecells, and fibroblasts) from the structural matrix without damaging thebiologic and structural integrity of the collagen matrix. Thedecellularization solution may contain an appropriate buffer, salt, anantibiotic, one or more detergents (e.g., TRITON X-100™, sodiumdeoxycholate, polyoxyethylene (20) sorbitan mono-oleate), one or moreagents to prevent cross-linking, one or more protease inhibitors, and/orone or more enzymes. In some embodiments, the decellularization solutioncomprises 1% TRITON X-100™ in RPMI media with Gentamicin and 25 mM EDTA(ethylenediaminetetraacetic acid). In some embodiments, the tissue isincubated in the decellularization solution overnight at 37 DC withgentle shaking at 90 rpm. In certain embodiments, additional detergentsmay be used to remove fat from the tissue sample. For example, in someembodiments, 2% sodium deoxycholate is added to the decellularizationsolution.

After the decellularization process, the tissue sample is washedthoroughly with saline. In some exemplary embodiments, e.g., whenxenogenic material is used, the decellularized tissue is then treatedovernight at room temperature with a deoxyribonuclease (DNase) solution.In some embodiments, the tissue sample is treated with a DNase solutionprepared in DNase buffer (20 mM HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 20 mM CaCl2 and 20mM MgCl2). Optionally, an antibiotic solution (e.g., Gentamicin) may beadded to the DNase solution. Any suitable buffer can be used as long asthe buffer provides suitable DNase activity.

Elimination of the α-gal epitopes from the collagen-containing materialmay diminish the immune response against the collagen-containingmaterial. The α-gal epitope is expressed in non-primate mammals and inNew World monkeys (monkeys of South America) as well as onmacromolecules such as proteoglycans of the extracellular components. U.Galili et al., J. Biol. Chem. 263: 17755 (1988). This epitope is absentin Old World primates (monkeys of Asia and Africa and apes) and humans,however. Id. Anti-gal antibodies are produced in humans and primates asa result of an immune response to α-gal epitope carbohydrate structureson gastrointestinal bacteria. U. Galili et al., Infect. Immun. 56: 1730(1988); R. M. Hamadeh et al., J. Clin. Invest. 89: 1223 (1992).

Since non-primate mammals (e.g., pigs) produce α-gal epitopes,xenotransplantation of collagen-containing material from these mammalsinto primates often results in rejection because of primate anti-Galbinding to these epitopes on the collagen-containing material. Thebinding results in the destruction of the collagen-containing materialby complement fixation and by antibody dependent cell cytotoxicity. U.Galili et al., Immunology Today 14:480 (1993); M. Sandrin et al., Proc.Natl. Acad. Sci. USA 90: 11391 (1993); H. Good et al., Transplant. Proc.24: 559 (1992); B. H. Collins et al., J. Immunol. 154: 5500 (1995).Furthermore, xenotransplantation results in major activation of theimmune system to produce increased amounts of high affinity anti-galantibodies. Accordingly, in some embodiments, when animals that produceα-gal epitopes are used as the tissue source, the substantialelimination of α-gal epitopes from cells and from extracellularcomponents of the collagen-containing material, and the prevention ofre-expression of cellular α-gal epitopes can diminish the immuneresponse against the collagen-containing material associated withanti-gal antibody binding to α-gal epitopes.

To remove α-gal epitopes, after washing the tissue thoroughly withsaline to remove the DNase solution, the tissue sample may be subjectedto one or more enzymatic treatments to remove certain immunogenicantigens, if present in the sample. In some embodiments, the tissuesample may be treated with an α-galactosidase enzyme to eliminate α-galepitopes if present in the tissue. In some embodiments, the tissuesample is treated with α-galactosidase at a concentration of 300 U/Lprepared in 100 mM phosphate buffer at pH 6.0. In other embodiments, theconcentration of α-galactosidase is increased to 400 u/L for adequateremoval of the α-gal epitopes from the harvested tissue. Any suitableenzyme concentration and buffer can be used as long as sufficientremoval of antigens is achieved.

Alternatively, rather than treating the tissue with enzymes, animalsthat have been genetically modified to lack one or more antigenicepitopes may be selected as the tissue source. For example, animals(e.g., pigs) that have been genetically engineered to lack the terminalα-galactose moiety can be selected as the tissue source. Fordescriptions of appropriate animals see co-pending U.S. application Ser.No. 10/896,594 and U.S. Pat. No. 6,166,288, the disclosures of which areincorporated herein by reference in their entirety.

After the acellular tissue matrix is formed, histocompatible, viablecells may optionally be seeded in the acellular tissue matrix to producea graft that may be further remodeled by the host. In some embodiments,histocompatible viable cells may be added to the matrices by standard invitro cell co-culturing techniques prior to transplantation, or by invivo repopulation following transplantation. In vivo repopulation can beby the recipient's own cells migrating into the acellular tissue matrixor by infusing or injecting cells obtained from the recipient orhistocompatible cells from another donor into the acellular tissuematrix in situ. Various cell types can be used, including embryonic stemcells, adult stem cells (e.g. mesenchymal stem cells), and/or neuronalcells. In various embodiments, the cells can be directly applied to theinner portion of the acellular tissue matrix just before or afterimplantation. In certain embodiments, the cells can be placed within theacellular tissue matrix to be implanted, and cultured prior toimplantation.

Particulate ATM can be made from any of the above describednon-particulate ATMs by any process that results in the preservation ofthe biologic and structural functions described above. As used herein,particulate ATMs are those particulate or pulverized (powdered) matriceshaving a longest dimension of 1.0 mm or less.

In some embodiments, particulate ATM used in the present disclosure ismanufactured so as to minimize damage to collagen fibers, includingsheared fiber ends. As a non-limiting example of a suitable method formaking particulate ATM is described in U.S. Pat. No. 6,933,326. Theparticle size for Cymetra is in the range of about 60 microns to about150 microns as determined by mass spectrophotometry.

Non-Biologic Component:

The at least one non-biologic component of the present disclosure may,for example, comprise biocompatible natural and/or synthetic materials.Biocompatible natural materials may include, for example, collagen,fibrin, and silk. Biocompatible synthetic materials may include, forexample, bioabsorbable polymers, non-bioabsorbable polymers, andmetallic alloys or compositions. In some embodiments of the presentdisclosure, a non-biologic component that is biocompatible andbioabsorbable is used. Utilizing bioabsorbable polymers may allow for atransfer of loads from the non-biologic component (e.g., the polymer) tothe biologic component as native tissue regenerates throughout thematrix structure of the biologic component.

As used herein, a “biocompatible” composition is one that has theability to support cellular activity necessary for complete or partialtissue regeneration, but does not stimulate an unacceptable inflammatoryor immunological response in the host. The term, “unacceptable localinflammatory or immunological response in the host” means a local orsystemic inflammatory or immunologic response that prevents tissueregeneration.

As used herein, the term “bioabsorbable” means that a material can beabsorbed by a mammalian body via biologically mediated degradationprocesses, such as enzymatic and cellular processes and/or chemicallymediated degradation processes. Such processes include, for example,degradation processes wherein the degradation products are excretedthrough one of the body's organ systems or in which the degradationproducts are incorporated into normal metabolic pathways.

In some embodiments, a suitable bioabsorbable material for use in thepresent disclosure, is made of a poly-hydroxybutyrate (apolyhydroxyalkanoate), such as the TephaFlex polymer produced by Tepha,Inc. of Cambridge, Mass. In some embodiments, useful bioabsorbablematerials include, for example, polylactic acid (PLA), polyglycolic acid(PGA), polylactideglycolide acid (PLGA), polydioxanone (PDO), orpolycaprolactone (PCL). In some embodiments, bioabsorbable materialssuitable for use in the present disclosure include polyanhydrides,polyorthoesters, poly(amino acids), polypeptides, polydepsipeptides,nylon-2/nylon-6coplyamides, poly(alkylene succinates), poly(hydroxylbutyrate) (PHB), poly (butylene diglocolate), poly (C-caprolactone),polydihydropyrans, polyphosphazenes, poly (ortho ester), poly (cyanoacrylates), modified polysaccharides, cellulose, starch, chitin,modified proteins, collagen, fibrin, and combinations and copolymersthereof. Non-limiting examples of non-bioabsorbable materials includenoble metals such as gold, as well as the near noble metals.

In some embodiments, synthetic polymers that may be used in accordancewith the present disclosure include those listed in U.S. Pat. No.5,885,829, the disclosure of which is incorporated herein by referencein its entirety.

The non-biologic components used herein may be provided in any form. Insome embodiments, the non-biologic components are in the form of amolded shape (e.g., as a single contiguous polymeric piece). Further, insome embodiments, the non-biologic components are in the form of atextile comprised of multiple yarns, the yarn being either amonofilament or a multifilament structure (such as a braid). Textilemanufacturing methods can then make final structures that are knitted,woven, braided, nonwoven, or combinations thereof.

Although the present disclosure has been described with reference tocertain non-limiting embodiments, other implementations are possible.For example, the composite material may be used for many applicationswhere soft tissues need to be replaced and yet provide specificload-carrying or biomechanical characteristics, including ligament,tendon or soft tissue replacement about the knees, ankles, shoulders,neck, and spine. Other hybrid systems can be developed utilizing thesame basic ideas as described above. Examples include: artificialmeniscus replacement or repair; abdominal wall (e.g., hernia) repair;cartilage repair in, for example, knees, shoulders and hips; jointresurfacing (instead of removing joints, the joint articulating surfacecan simply be covered with a composite material reinforced with fabricusing appropriately designed anchors or sutures); and pace maker pouches(a simple bag/pouch used to contain pacers or pain manager systems wouldmake periodic replacement much simpler and would create a more stableanchor pacer implant).

Accordingly, other embodiments will be apparent to those skilled in theart from consideration of the specification disclosed herein. It isintended that the specification and embodiments disclosed herein beconsidered as exemplary only, with a true scope being indicated by thefollowing claims.

What is claimed is:
 1. An implantable medical device, comprising: agroup of first elongate non-biologic elements; a sheath wrapped aroundand surrounding at least a portion of the group of first elongatenon-biologic elements; and at least one second elongate non-biologicelement, wherein the at least one second element secures at least oneend portion of the group of first elongate non-biologic elements.
 2. Theimplantable medical device of claim 1, wherein at least a portion of thegroup of first elongate non-biologic elements are under a tensile orcompressive stress prior to implantation.
 3. The implantable medicaldevice of claim 2, wherein at least a portion of the group of firstelongate non-biologic elements are loaded with the tensile orcompressive stress independently of the sheath.
 4. The implantablemedical device of claim 1, wherein at least a portion of the group offirst elongate non-biologic elements and the sheath are loaded togetherwith a tensile or compressive stress.
 5. The implantable medical deviceof claim 2, wherein the group of first elongate non-biologic elementshave a higher load capacity than the sheath at the time of implantation.6. The implantable medical device of claim 5, wherein the sheath has ahigher load capacity than the group of first elongate non-biologicelements after implantation and following growth of native cells withinthe sheath.
 7. The implantable medical device of claim 1, wherein thesheath comprises a non-biologic material.
 8. The implantable medicaldevice of claim 1, wherein the sheath comprises a biologic componentincluding a biomatrix.
 9. The implantable medical device of claim 8,wherein the biomatrix comprises an acellular tissue matrix or aparticulate acellular tissue matrix.
 10. The implantable medical deviceof claim 1, wherein the at least one second elongated non-biologicelement is wrapped around and over the sheath to secure at least one endportion of the group of first elongate non-biologic elements.
 11. Theimplantable medical device of claim 1, wherein the sheath forms a singlelayer over the group of first elongate non-biologic elements.
 12. Theimplantable medical device of claim 1, wherein the sheath is wrapped ina jellyroll fashion with multiple layers over the group of firstelongate non-biologic elements.
 13. The implantable medical device ofclaim 1, wherein the sheath is wrapped in a non-uniform jellyrollfashion with multiple non-concentric layers over the group of firstelongate non-biologic elements.
 14. The implantable medical device ofclaim 1, comprising an outer sheath wrapped around and surrounding atleast a portion of the sheath.
 15. The implantable medical device ofclaim 1, wherein the group of first elongate non-biologic elementscomprise at least one material chosen from bioabsorbable polymer,bioabsorbable metal, or a combination of bioabsorbable polymer andbioabsorbable metal.
 16. The implantable medical device of claim 1,wherein the group of first elongate non-biologic elements comprise atleast one material chosen from polyhydroxyalkanoate,poly-hydroxybutyrate, polylactic acid (PLA), polyglycolic acid (PGA),polylactideglycolide acid (PLGA), polydioxanone (PDO), polycaprolactone(PCL), a polyanhydride, a polyorthoester, a poly(amino acid), apolypeptide, a polydepsipeptide, a nylon-2/nylon-6 copolyamide, apoly(alkylene succinate), poly(hydroxyl butyrate) (PHB), poly(butylenediglocolate), poly(.epsilon.-caprolactone), a polydihydropyran, apolyphosphazene, a poly(cyano acrylates), modified polysaccharides,cellulose, starch, chitin, modified proteins, collagen, fibrin, andcombinations and copolymers thereof.
 17. The implantable medical deviceof claim 1, wherein the group of first elongate non-biologic elementscomprise a bioabsorbable polymer, a bioabsorbable metal or a combinationof a bioabsorbable polymer and bioabsorbable metal.
 18. The implantablemedical device of claim 2, wherein the group of first elongatenon-biologic elements are under a tensile stress ranging from greaterthan 0 N to about 1800 N.
 19. The implantable medical device of claim 1,wherein the group of first elongate non-biologic elements comprise aplurality of threads, cords, cables, ribbons, or braids.
 20. Animplantable medical device, comprising: a group of first elongatenon-biologic elements, at least a portion of which are under a tensileor compressive stress prior to implantation; a sheath wrapped around andsurrounding at least a portion of the group of first elongatenon-biologic elements; and at least one second elongate non-biologicelement, wherein the at least one second element secures at least oneend portion of the group of first elongate non-biologic elements;wherein the group of first elongate non-biologic elements have a higherload capacity than the sheath at the time of implantation; and whereinthe sheath has a higher load capacity than the group of first elongatenon-biologic elements after implantation and following growth of nativecells within the sheath.